The long-term objective of this program is the development of effective vaccines against HIV using novel recombinant viral vectors. Toward this end, the goals of this proposal are to attain a better understanding of the protective immune responses against HIV and to design novel antigen configurations and improved vectors to elicit these protective immune responses. The combined projects of this program have five major specific aims: 1. Comparison of the immune responses against HIV in individuals that exhibit long-term non-progressive HIV infection with those that have normal progression of HIV infection. 2. Modification of HIV and SIV genes to enhance antigen presentation, insertion of these altered genes into poxvirus vectors, and assessment of these recombinant viruses in rodents. Such modifications are aimed at increasing protein processing, enhancing or redirecting intracellular transport, or exposing sequestered epitopes. Co-stimulatory molecules will be included to enhance cellular immune responses. 3. Expression of genes encoding potent antibodies to neutralize HIV. Genes encoding broadly neutralizing antibodies will be inserted into recombinant adeno-associated virus to deliver high levels of neutralizing antibodies to the circulation. 4. Development of improved live recombinant viral vectors and better animal models for AIDS vaccines. Vectors include adeno-associated virus, non-replicating pox-viruses and replication pox-viruses that lack factors involved in evading the host immune response. A scid mouse model will be improved to enhance engraftment and allow induction of primary immune responses. 5. Design and manufacture of new candidate AIDS vaccines for clinical trials in humans. Second-generation vaccines will be generated immediately, based on current knowledge. Third-generation vaccines will be designed after accumulating additional information on correlates of immunity, optimal antigen conformation, combinations with immunomodulatory molecules, and viral vector improvements.